Striatal origin of the pathologic beta oscillations in Parkinson's disease

Abstract

Enhanced oscillations at beta frequencies (8-30 Hz) are a signature neural dynamic pathology in the basal ganglia and cortex of Parkinson's disease patients. The mechanisms underlying these pathological beta oscillations remain elusive. Here, using mathematical models, we find that robust beta oscillations can emerge from inhibitory interactions between striatal medium spiny neurons. The interaction of the synaptic GABAa currents and the intrinsic membrane M-current promotes population oscillations in the beta frequency range. Increased levels of cholinergic drive, a condition relevant to the parkinsonian striatum, lead to enhanced beta oscillations in the striatal model. We show experimentally that direct infusion of the cholinergic agonist carbachol into the striatum, but not into the neighboring cortex, of the awake, normal rodent induces prominent beta frequency oscillations in the local field potential. These results provide evidence for amplification of normal striatal network dynamics as a mechanism responsible for the enhanced beta frequency oscillations in Parkinson's disease.

Fig. 1.

Beta oscillations emerge in the model striatum under normal conditions and become enhanced under parkinsonian conditions. A–E are taken from the same 7-s simulation under normal conditions, and F–J are from the same 7-s simulation under parkinsonian conditions. (A) Raster plot of 100 reciprocally connected medium spiking neurons (MSNs) under normal, non-parkinsonian conditions. (B) Power spectral density of the model LFP. (C) Spectrogram of the model LFP. (D) Membrane voltage fluctuations from one MSN in the network. (E) Waxing and waning of the model LFP trace under normal conditions. (F) Raster plot of 100 reciprocally connected MSNs under parkinsonian conditions. (G) Power spectral density of the model LFP. (H) Spectrogram of the model LFP. (I) Membrane voltage fluctuations from one MSN in the parkinsonian network. (J) The model LFP trace under parkinsonian conditions.

Fig. 2.

Enhanced beta oscillations emerge in striatal LFP after carbachol infusion. (A) Power spectrum of the LFP recorded in the striatum of an awake, head-fixed mouse before, during, and after striatal carbachol infusion. (Upper) LFP power spectrum at 3–70 Hz on a log scale. (Lower) LFP power at beta frequency (10–30 Hz). (B and C) Power spectrum and LFP during a representative time window before carbachol infusion. (Upper) Power spectrum. (Lower) Corresponding LFP recorded in the striatum. (D and E) Power spectrum and LFP during a representative time window upon carbachol infusion. (Upper) Power spectrum. (Lower) Corresponding LFP recorded in the striatum. (F) Beta frequency power of the LFP recorded in the striatum before, during, and after carbachol (0.5–1.0 mM) infusion in the striatum (n = 6 mice; ***P < 0.005 and *P < 0.05 paired t test compared to the power before carbachol infusion). (G) Beta frequency power of LFP recorded in the striatum before, during, and after low concentration carbachol (0.1–0.2 mM) infusion in the striatum (n = 5 mice). (H) Beta frequency power of LFP recorded in the cortex before, during, and after carbachol (1 mM) infusion in the cortex (n = 5 mice). (I) Beta frequency power of LFP recorded in the striatum before, during, and after carbachol (1 mM) infusion in the cortex (n = 5 mice).